The invention relates to chemical modification of cellulosic dialysis membranes for improvement of biocompatibility.
U.S. Pat. No. 3,745,202 and German Offenlegungsschrift No. 2,300,496 describe processes for making asymmetric membranes from celluose derivatives containing ester and/or ether groups.
German Pat. No. 2,705,735 discloses a dialysis membrane for hemodialysis, having antithrombogenic compounds chemically bonded thereto, the dialysis membrane consisting of two or more layers of a cellulose regenerated from cuprammonium cellulose solutions, each of which has been obtained from separately fed orifices of a spinneret, which cellulose contains chemically bonded substances having antithrombogenic activity.
German Offenlegungsschrift No. 2,748,858 describes the preparation of antithrombogenic polymer materials which are prepared by the following procedure:
reaction of reactive polymers with synthetic fibrinolytic compounds (covalent bonding), PA1 treatment of polymers containing anion-exchange groups with a synthetic fibrinolytic compound (ionic bonding), PA1 treatment of polymer materials with solutions of synthetic fibrinolytic compounds (adsorption). PA1 X represents --NR"-- and/or --N.sup.+ R".sub.2 -- and/or --S-- and/or --SO-- and/or --SO.sub.2 -- and/or --CO--NR-- and/or --CO--O-- and/or --O--, PA1 Y represents --R and/or --NR.sub.2 and/or --Si(OR").sub.3 and/or --SO.sub.3 H and/or --COOH and/or --PO.sub.3 H.sub.2 and/or --N.sup.+ HR.sub.2 and the salts thereof, PA1 R' represents an alkylene group and/or cycloalkylene group and/or arylene group having a total of from 1 to 25 C atoms, PA1 R" represents a hydrogen atom or R, and PA1 R represents an alkyl group having 1 to 5 C atoms and/or a cycloalkyl group and/or aryl group. PA1 X denotes --H, --NR.sub.2, --N.sup.+ R.sub.3, --CN, --COOH, --SO.sub.3 H, --PO(OR).sub.2, --CONR.sub.2 or --Si(OR).sub.3, where R denotes a hydrogen atom or an alkyl or alkenyl group having from 1 to 25 C atoms, or a cycloalkyl, tolyl or phenyl group, and PA1 Y is an alkyl, alkenyl or alkynyl group, which may or may not be substituted, having from 1 to 36 C atoms, a cycloalkyl group or a phenyl, tolyl or benzyl group or a ##STR2## or (--CH.dbd.CH--COOH) or NH--R radical and R has the same meaning as above, and PA1 r=1-20, PA1 m=0-2.5, PA1 n=0.2 to 2.95, PA1 R' is CH.sub.3 and/or C.sub.2 H.sub.5 and/or C.sub.3 H.sub.7, PA1 X is a specified functional group, and PA1 R" is H or R, PA1 x+t=1.00 to 2.50, PA1 x=0 to 0.5 t, PA1 r=0.01 to 0.45, PA1 R' is CH.sub.3 and/or C.sub.2 H.sub.5 and/or C.sub.3 H.sub.7, PA1 X is a specified functional group, and PA1 m=1.00 to 2.50, PA1 x=0.01 to 0.45, PA1 R' is CH.sub.3 and/or C.sub.2 H.sub.5 and/or C.sub.3 H.sub.7, PA1 X is a specified functional group, and PA1 Z corresponds to the following groups of atoms: SR", SO.sub.3 H or a salt thereof, SO--R, SONR".sub.2, SO.sub.2 --R, SO.sub.2 NR".sub.2, SO.sub.2 H or a salt thereof, F, Cl, Br, I, NR".sub.2, PR".sub.2, PO.sub.3 H.sub.2 or a salt thereof, PO.sub.2 H(OR), PO(OR).sub.2, PO.sub.2 HR" or a salt thereof, POR"(OR), POR".sub.2, PA1 R" is H or R, PA1 x+t=1.0 to 2.50, PA1 x=0 to 0.5 t, PA1 z=0.01 to 0.45,
Such a membrane modification is ruled out, because biocompatibility-improving compounds which are bound only adsorptively to the polymer can pass into the bloodstream during dialysis.
U.S. Pat. No. 3,475,410 and the paper in Vol. XII Trans. Amer. Soc. Artif. Int. Organs, 1966, pp. 139-150 describe antithrombogenic cellulose membranes which are obtained by treatment of cellulose first with ethyleneimine and then with heparin. According to our investigations, however, membranes modified with ethylamino groups have poorer biocompatibility than unmodified membranes.
Japanese Applications JP Nos. 57-162,701 and 57-162,702 also claim antithrombogenic cellulose membranes. These are prepared by grafting vinyl monomers onto cellulose or cellulose derivatives, followed by heparinization. In addition to the grafting reaction, however, it is known that a homopolymerization can also occur. Although no permanent bond exists between the homopolymer and the cellulose, the homopolymer cannot be removed completely from the membrane despite intensive washing. Therefore small quantities of the homopolymer can always pass into the blood-stream during blood dialysis.
Japanese Patent Application No. 60-203,265 describes high molecular weight cellulose products for the preparation of medical instruments with anticoagulant properties. Such products are mixtures of polycationic anc polyanionic cellulose derivatives, and are usually obtained by mixing appropriate polymer solutions. Such water-insoluble salts are unsuitable as membrane materials, since the danger is always present that they will be transformed by salt-interchange effects into a compound which is water-soluble or which swells greatly in water.
However, it has also been proposed in German Offenlegungsschrift No. 1,720,087 that by reacting the polymeric material of the membrane with an alkyl halide and then reacting the resulting material with an alkali metal salt of an antithrombogenic compound having a cationic residue (for example, heparin or a heparinoid compound) the risk of blood coagulation is diminished. The possible alkyl halides in this context also include haloalkyldialkylamines. Cellulose and cellulose acetate are among the possible polymers.
An antithrombogenic effect of these known dialysis membranes is observed only when the degree of substitution of the modified cellulose is high, i.e., greater than at least 0.1, and a preheparinization with a relatively high heparin concentration (0.1 to 1% by weight solution) is carried out in a separate stage.
German Offenlegungsschrift No. 3,341,113 discloses a dialysis membrane in the form of flat films, tubular films or hollow filaments of regenerated cellulose, in which polymeric acids are chemically bonded to at least one membrane surface by means of bridge-forming agents which are chemically bonded to the cellulose. Aside from the fact that the preparation is relatively expensive even though it is carried out in a post-treatment, the effectiveness is essentially limited to reduction of leukopenia. Because of the large molecules of the polymeric acids, bonding by means of bridge-forming agents occurs only at the surface of the membrane.
German Offenlegungsschrift No. 3,438,531 discloses a dialysis membrane in which isocyanate prepolymers are bonded to cellulose. The effectiveness is limited in a manner similar to that for the above-mentioned cellulose membrane modified with polymeric acids.
German Offenlegungsschrift No. 3,524,596 discloses a dialysis membrane with improved biocompatibility, which is distinguished in that the mean degree of substitution of a modified cellulose is from 0.02 to 0.07. The known dialysis membrane composed of modified cellulose preferably contains such a modified cellulose which has a structure represented by the formula EQU cellulose--R'--X--Y
where
This known dialysis membrane is capable of reducing to a considerable extent blood coagulation, leukopenia and complement activation. However, no noteworthy extent of adsorption of beta-2-microglobulin has been achieved.
German Patent Application No. P 3,723,897.3 describes cellulose derivatives having the general formula ##STR1## in which --Z-- denotes an alkylene, alkenylene, alkynylene, cycloalkylene or benzylene or xylylene radical which may or may not be substituted,
with the proviso that, where m=0, n&gt;1.55 when Y is an alkyl radical having 1-5 C atoms, a --(CH.sub.2).sub.r --COOH radical with r=0, 1 or 2 or a radical of phthalic acid, and the degree of polymerization is more than 400, and which can be prepared by homogeneous reaction in a mixture of dimethyl acetamide and/or N-methylpyrrolidone with LiCl after activation of the cellulose starting material without the presence of LiCl, the preparation thereof and the use thereof for membranes and filaments.
German Patent Application No. P 3,805,992.4 relates to modified cellulose for biocompatible dialysis membranes, which cellulose has a structure represented by the formula ##STR3## wherein Cell is cellulose or chitin, in each case without hydroxyl groups, s=3 in the case of cellulose and s=2 in the case of chitin, and
wherein
and the degree of polymerization (DP) is 100 to 500, as well as a process for preparation of the cellulose derivatives.
German Patent Application No. P 3,805,966.5 relates to modified cellulose for biocompatible dialysis membranes, which cellulose has a structure represented by the formula ##STR4## wherein Cell is unmodified cellulose or chitin, in each case without hydroxyl groups, s=3 in the case of cellulose and s=2 in the case of chitin, and
wherein
and the degree of polymerization (DP) is 100 to 500, as well as a process for preparation of the modified cellulose derivatives.
German Patent Application No. P 3,805,973.8 relates to modified cellulose for biocompatible dialysis membranes, wherein the modified cellulose has a structure represented by the formula ##STR5## wherein Cell is cellulose or chitin, in each case without hydroxyl groups, s=3 in the case of cellulose and s=2 in the case of chitin, and
wherein
wherein
and the degree of polymerization (DP) is 100 to 500, as well as a process for preparation of the cellulose derivatives.
Apart from the circumstance that dialysis membranes composed of synthetic or natural polymers can, when used in artificial kidneys, very easily induce blood coagulation, which is substantially prevented by appropriate drug treatment, in the case of dialysis membranes composed of regenerated cellulose there is frequently a transient fall in leukocytes in the first period of dialysis treatment when a kidney patient is treated with dialyzers having cellulose membranes. This effect is called leukopenia. Leukopenia is a reduction in the number of leukocytes (white blood corpuscles) in the circulating blood. The number of white blood corpuscles in humans is about 4,000 to 12,000 cells/mm.sup.3.
Leukopenia associated with dialysis is most pronounced 15 to 20 min after the start, it being possible for the neutrophils (which are the leukocytes which can be stained with neutral or simultaneously with acidic and basic dyes) to disappear almost completely. Subsequently, the number of leukocytes recovers again within about one hour to almost the initial level or exceeds it.
If, after the leukocytes have recovered, a new dialyzer is connected, leukopenia occurs again to the same extent.
Cellulose membranes cause pronounced leukopenia. Even though the clinical significance of leukopenia has not been scientifically elucidated, there is nevertheless a desire for a dialysis membrane for hemodialysis which does not exhibit the leukopenia effect, without this adversely affecting the other very desirable properties of dialysis membranes composed of regenerated cellulose.
During hemodialysis using membranes composed of regenerated cellulose, beside the leukopenia there has also been found a distinct complement activation. The complement system within the blood serum is a complex plasma-enzyme system which consists of many components and acts in various ways to prevent damage due to invading foreign cells (bacteria etc.). When antibodies against the invading organism are present, there can be complement-specific activation by the complex of the antibodies with antigenic structures of the foreign cells, otherwise complement activation takes place by an alternative pathway due to special surface features of the foreign cells. The complement system is based on a multiplicity of plasma proteins. After activation, these proteins react specifically in a defined sequence with one another and, finally, a cell-damaging complex which destroys the foreign cell is formed.
Individual components release peptides which induce inflammatory manifestations and occasionally can also have undesired pathological consequence for the organism. It is assumed that in the case of hemodialysis membranes composed of regenerated cellulose the activation takes place by the alternative pathway. These complement activations are detected objectively by determination of the complement fragments C3a and C5a.
In this context, reference is made to the following studies: D. E. Chenoweth et al., Kidney International, vol. 24, pages 746 et seq., 1983 and D. E. Chenoweth, Asaio-Journal, vol. 7, pages 44 et seq., 1984.
The carpal tunnel syndrome is affected by modified cellulose derivatives. Yet, there is a considerable need for further modifications of the cellulose in order to eliminate this phenomenon too as completely as possible.